In last month’s issue of the Journal, we published Part I of this article. This month’s conclusion focuses on other risk stratification models and tools. Several major studies have established the benefit of glycoprotein (GP) IIb/IIIa inhibitors in the management of patients with ACS in addition to standard medical therapy (aspirin and heparin ± beta-blocker) with or without percutaneous coronary intervention (PCI).42–45 Subgroup analyses of patients with elevated cardiac troponin levels in two of these studies [CAPTURE (cTnT) and PRISM (cTnI)] have shown a remarkable benefit from GP IIb/IIIa treatment in patients with elevated troponin level, with no significant benefit in patients with normal cTn levels.46,47 The debate about the ideal approach for the management of patients with UA/non-Q wave MI (i.e., early invasive versus early conservative) has been ongoing for the past decade.48–50 More recently, the TACTICS-TIMI 18 trial51 has conclusively shown that an early invasive approach using the GP IIb/IIIa inhibitor tirofiban and coronary stenting in addition to standard medical therapy (aspirin + heparin ± beta-blocker) is superior to early conservative management (aspirin + heparin + tirofiban ± beta-blocker). A subgroup analysis of patients with elevated cTnT levels has shown a remarkable 40% relative risk reduction of cardiac events (death, MI, rehospitalization for ACS) at 6 months with early invasive management compared to early conservative management, whereas patients with normal cTnT level did not receive any benefit from early invasive approach. These data support an aggressive management approach that includes using enoxaparin, GP IIb/IIIa inhibitor, and early invasive approach in UA/NSTEMI patients presenting with elevated cardiac troponin level, and justify withholding such expensive and invasive treatments from lower-risk “troponin-negative” patients awaiting further non-invasive risk stratification data to determine further management (Figure 7). It is worth mentioning that the presented data, which substantiated the value of cardiac troponins in risk stratification in UA/NSTEMI, have been derived from large, randomized clinical trials with strict entering criteria. Most patients enrolled in these studies had known CAD, or indicators of severe UA (ECG changes or prolonged chest pain). This may minimize the value of cardiac troponin in very low-risk patients, such as those presenting with “atypical chest pain” or those presenting predominantly with symptoms of heart failure. On the other hand, the value of normal troponin level in otherwise high-risk patients is also unclear. Nevertheless, the value of cardiac troponins in risk stratifying patients UA/NSTEMI is undisputable and they should be the cornerstone of any risk stratification scheme. New risk stratification models TIMI risk score. Based on the unfractionated heparin group cohort of the TIMI-11B trial,39 the TIMI group derived a risk stratification scheme and risk score (TIMI risk score).52 Using multivariate logistic regression analysis, they identified 7 factors to be independent predictors of a composite endpoint of all-cause mortality, myocardial infarction and severe recurrent ischemia prompting urgent revascularization. These factors are: 1) age >= 65 years; 2) at least 3 risk factors for CAD (family history, diabetes, hypertension, hypercholesterolemia, current smoking); 3) significant coronary stenosis (prior known coronary stenosis >= 50%); 4) ST deviation; 5) severe anginal symptoms (>= 2 anginal events in the last 24 hours); 6) use of aspirin in the last 7 days; and 7) elevated serum cardiac markers (CK-MB and/or cardiac-specific troponin level). By assigning 1 point for each of these factors, a risk score could be calculated simply by adding points assigned for each risk factor in a given patient (range from 0–7 points). Event rates increased significantly as the TIMI risk score increased: 4.7% for risk score of 0/1; 8.3% for risk score of 2; 13.2% for risk score of 3; 19.9% for risk score of 4; 26.2% for risk score of 5; and 40.9% for risk score of 6/7 (p = 4 predicts benefit from the GP IIb/IIIa inhibitor tirofiban.57 PURSUIT risk stratification model. The PURSUIT trial was a randomized, double-blinded, controlled clinical trial that compared the GP IIb/IIIa inhibitor eptifibatide to placebo in the management of patients with UA/NSTEMI.44 Using multivariate logistic regression analysis, the PURSUIT investigators have identified several risk predictors for the composite of death and MI at 30 days in 9,461 patients participating in the trial. They then validated these risk predictors by bootstrapping techniques.58 The most important predictors for the mortality or the composite of death or MI at 30 days identified were old age, tachycardia, low systolic blood pressure, ST-segment depression, signs of heart failure and elevated cardiac enzymes (CK-MB). Using some of these factors, they developed a risk scoring system to predict risk of death or the composite of death and MI at 30 days. Calculating this risk score is more demanding; hence, it did not gain popularity among clinicians. The apparent drawback to this scoring system is that it did not include cardiac troponin as a crucial risk predictor. Furthermore, the interaction between this score and the benefit from various treatments and interventions available for patients with UA/NSTEMI has not been evaluated. ACC/AHA guidelines risk stratification model. Considering the huge mass of data for risk stratification in unstable angina, the ACC/AHA task force on UA/NSTEMI has incorporated some of the emerging data, especially cardiac troponin and prior aspirin use, into the AHCPR model adopting the ACC/AHA guidelines on risk stratification of patients with UA/NSTEMI (Table 3).8 As in the AHCPR model, patients are categorized into 3 risk categories (low, intermediate, high) addressing short-term risk of death or nonfatal MI. Although the individual risk factors that constitute this model have been validated in prior studies, this entire model has not yet been prospectively validated. Other risk stratification tools Continuous 12-lead ECG monitoring for recurrent ischemic episodes identified by a computer algorithm in the early hours (24–48 hours) after admission has been shown to be an indicator of early (5 days) and long-term (30 days, and 6 months) risk for death and MI.58–61 This is especially valuable in combination with cardiac troponins.59 The inherent delay to acquire this prognostic information (24–48 hours) has limited its use in clinical practice, as most physicians thrive for early risk stratification to improve outcome and limit cost. In the past few years, there has been emerging evidence that elevated inflammation markers in the blood are an indicator of atherosclerotic plaque instability. Several acute-phase reactants, such as high-sensitivity C-reactive protein (C-RP), fibrinogen level, and serum amyloid-A, have been shown to be independent risk predictors in ACS.37,62,63 Among these factors, C-RP is the best studied. Several studies have shown that C-RP level has an incremental prognostic value to cardiac troponins. Patients presenting with UA but with a normal troponin level have several-fold increase in risk of cardiac events if they have an elevated C-RP value, compared to those with normal value. In fact patients with negative troponin and elevated C-RP have a similar event rate to those with positive troponin. Patients with elevated C-RP and cardiac troponin levels are at higher risk of cardiac events than those with elevated troponin but normal C-RP level (Figure 10).37,62 Data from the major lipid lowering secondary prevention trials showed that HMG Co-A inhibitors (statins) lower C-RP level by 15–20%.64,65 Recent data from the MIRACLE trial66 have shown that early aggressive lipid lowering using the high-dose HMG Co-A inhibitor atorvastatin in patients with non-ST elevation MI is associated with a lower rate of future ischemic events compared to conventional cholesterol lowering according The National Cholesterol Education Program (NCEP) guidelines.67 Although these data are very compelling, the interplay between serum cholesterol, C-RP, lipid lowering agents and improved outcome in patients with acute coronary syndrome is yet unclear. It is also unclear how to incorporate these data in the decision-making process, and whether it alters the management of patients with ACS. More studies are still needed to answer this question. Very recently, brain (B-Type) natriuretic peptide level (BNP) has been shown to correlate well with mortality in patients with ACS.68 The clinical value of this factor in clinical practice and its interplay with other predictors is yet unclear. Comparison between the existing risk stratification models using and evidence-based approach When assessing the value of risk prediction models, several authors have offered criteria for this purpose. As we compare models, the following criteria are worth reviewing. Was a representative group of patients completely followed up? Were all potential predictors included? Were the independent contributions of individual predictors tested? Were outcomes clearly identified? Does the model retain its power in another sample? How precise are the estimates? What is the threshold choice and what is its accuracy? Do the results apply to all patient subgroups? Finally, does the model improve clinical decision-making?69,70 Each of the models discussed above has some obvious strengths and weaknesses (Table 4). The AHCPR guidelines are highly dependent on physician’s ability to assess patient risk of CAD; in addition, it is not easy to use in daily clinical practice due to multiplicity of the determining risk factors. More importantly, it does not include cardiac troponins and prior aspirin use since it predated these data. Finally, it does not provide any numerical estimation of event rate in each category, which promotes variability in decision-making among physicians. Some of these gaps were clearly recognized by the ACC/AHA task force, which lead to the incorporation of cardiac troponin levels and prior aspirin use into its guidelines. Also, the guidelines have limited the need to assess CAD probability (as in the AHCPR guideline) and consequently limited the inter- and intra-clinician variability in assessing risk in UA/NSTEMI patients. Although the guideline contents are based on preexisting data, they have not yet been prospectively validated. The need for numerical risk estimation of event rate to enhance decision-making, made a risk score model with a corresponding estimated event rate an attractive approach. The RUSH model identified six easy to remember risk factors, and it provided the opportunity for calculating relative risk, or estimated event rate. The events used in this initial report were composite of death, MI, heart failure or ventricular arrhythmias (VT/VF). The model was statistically validated using a boot-strap model, and tested and compared in a separate sample. An important advantage of this model is that it was derived from patients who were admitted based on physician discretion, rather than strict predetermined entry criteria of a clinical trial, which made its sample a better representation of patients presenting to the emergency department (all comers). It has also addressed diabetes as an important risk predictor. Nevertheless, it does not integrate cardiac markers, limiting its value in current practice. Also, calculating estimated risk of cardiac events using this model is math-intensive and impractical in daily practice. The TIMI risk score provides an easy to use model compared to other models. Like other models, it has been prospectively validated. One of the drawbacks in this model is that some of its risk factors are not readily identifiable at presentation (e.g., known coronary stenosis >= 50%). Another important problem with this model is that it has been derived and validated from a randomized clinical trial (TIMI-11B) cohort, with predetermined inclusion criteria. Most patients enrolled in this trial had known coronary disease and/or other high-risk features (ECG changes or positive markers). This explains the scarcity of patients with a risk score of “0”, and the relatively high event rate noted in patients with low TIMI score (4.7% event rate for score of 0/1). Such an event rate is unacceptably high for most physicians to opt for outpatient management, which makes this model less valuable in identifying candidates for outpatient management. An important role for any “ideal” risk stratification scheme is targeting certain groups of patients with therapies that have been shown to benefit these particular groups, to improve the patient outcome, and identify those patients who would be candidates for outpatient management in order to minimize unnecessary resource utilization. Troponin levels can help guide therapy. It is evident that patients with elevated troponin level enjoy incremental risk reduction from enoxaparin, GP IIb/IIIa therapy and early invasive approach, compared to “troponin negative” patients. The value of targeting “troponin positive” patients with these treatments to alter their outcome cannot be over emphasized. There are also data to support the value of TIMI risk score in guiding therapy. Emerging data demonstrate incremental benefit from enoxaparin, GP IIb/IIIa inhibitor (tirofiban), and early invasive approach in patients with intermediate and high-risk scores. The current clinical trials in UA/NSTEMI are addressing the benefit of certain interventions in this patient population. Nevertheless, these data do not guide us in selecting the ideal treatment in an individual patient. It may be as important to prospectively compare different interventions in predefined risk groups of patients to determine the ideal therapeutic approach based on patient risk. Also, further studies may still be needed to accurately identify patients at low risk using a risk score or a combination of a clinical model and laboratory findings.70 Diabetes has been recognized as an important poor prognostic indicator in patients with UA/NSTEMI.18,71 More importantly, some recent data from PRISM-PLUS suggest that diabetic patients have incremental benefit from the GP IIb/IIIa receptor inhibitor tirofiban compared to non-diabetics.72,73 Nevertheless, it is unclear whether diabetes is an independent predictor of benefit from GP IIb/IIIa receptor inhibitors in patients who are otherwise low risk, or it is due to the fact that diabetics are prone to have extensive coronary artery disease and more likely to have elevated cardiac troponin level, an important predictor of GP IIb/IIIa receptor inhibitors benefit. More studies are needed to define the role of GP IIb/IIIa receptor inhibitors in this important group of patients. In the future, more studies are needed to address the issue of prior aspirin use, or aspirin resistance, where alternative methods of platelet suppression (e.g., clopidogrel, GP IIb/IIIa inhibitor), or more aggressive antithrombotic therapy (enoxaparin) may be beneficial. Also, more studies may be needed to understand the value of emerging risk factors such as C-RP, BNP, and their impact on decision-making. Suggested evidence-based algorithm for the assessment and management of patients with ACS From our experience at Cook County Hospital, we have adopted an evidence-based assessment and management algorithm that incorporates the current state of knowledge in the management of patients with ACS, as illustrated in Figure 7. This model coincides with the current ACC/AHA guidelines on this matter.8 The assessment of patients with UA/NSTEMI begins in the emergency department, as the clinical history, physical findings, initial ECG, and cardiac markers have an immense impact on patients triage and management. Those patients with clinical and/or laboratory findings diagnostic for UA/NSTEMI are classified as confirmed ACS. Patients with confirmed ACS and evidence of ST-elevation on ECG should be considered for reperfusion or revascularization therapy. Patients with atypical presentation and normal ECG and serum cardiac markers are classified as possible ACS. Patients with confirmed ACS, but no ST-elevation, are further classified based on their risk for further cardiac events. Those with high or intermediate risk features (i.e., ST depression >= 1 mm, T-wave inversion >= 2 mm deep, elevated serum cardiac markers, recent MI in the prior 2 weeks) are admitted to the coronary care unit or the cardiac step-down unit and treated immediately with aspirin, enoxaparin (or unfractionated heparin), beta-blocker, nitrate, and small molecule GP IIb/IIIa receptor inhibiter (eptifibatide or tirofiban). Adding clopidogrel as part of the medical management in this group of ACS patients should be considered, as recent data from the CURE trial have shown that this intervention reduces the risk of long term (1-year) cardiovascular events.74 These patients would undergo cardiac catheterization within 24 hours. Patients with refractory chest pain may undergo immediate or urgent cardiac catheterization and the decision to use the GP IIb/IIIa inhibitor abciximab is made in the cardiac catheterization laboratory if PCI is contemplated. Patients who did not receive small molecule GP IIb/IIIa inhibitor at presentation would receive this treatment in the cardiac catheterization laboratory if PCI is contemplated. Recent data from the TARGET trial suggest that abciximab (large molecule GP IIb/IIIa inhibitor) is superior to tirofiban in patients with ACS undergoing PCI.75 Patients with confirmed ACS with no high- or intermediate-risk features are admitted to a telemetry unit or a cardiac stepdown unit and treated with aspirin, enoxaparin (or unfractionated heparin), beta-blocker, and nitrate, but not IIb/IIIa receptor inhibiter. The decision to use an early invasive approach (angiogram within 24 hours) versus early conservative approach in this low-risk group is left to the physician’s clinical judgment or preference. If early conservative approach is chosen, left ventricular function and inducible ischemia are assessed within 24–48 hours after stabilization. Patients with impaired left ventricular systolic function or significant inducible ischemia on noninvasive testing would undergo cardiac catheterization. Patients who demonstrate symptoms of chest pain, congestive heart failure, ventricular arrhythmias, or hemodynamic instability despite medical management should also undergo immediate cardiac catheterization, whereas patients who respond to medical management with normal left ventricular function and minimal or no demonstrable ischemia on noninvasive testing can be treated medically. Patients with possible ACS are usually observed for at least 8 hours. Follow-up ECG and serum cardiac markers (CK-MB, cTn) are obtained after 4–8 hours. If repeat testing confirms ACS, these patients are managed using the same algorithm used for patients with confirmed ACS. In patients with nondiagnostic follow-up serum cardiac markers and ECG, non-invasive assessment for inducible ischemia should be performed in all patients. Assessment of left ventricular function is done in selected patients. The absence of inducible ischemia on noninvasive testing in these patients justifies early patient discharge, and an alternative diagnosis for chest pain should be considered. Implementation of this approach achieves several objectives: 1) targeting intermediate- and high-risk patients to receive GP IIb/IIIa receptor antagonists and early invasive strategy, which have been shown to improve the outcome of these patients; 2) limiting the use of unnecessary invasive interventions and costly medical therapies in low-risk patients, but identifying those low-risk patients who would benefit from such interventions; 3) early discharge of low-risk patients and those with noncardiac chest pain with a huge consequent saving in healthcare dollars.
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